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Background: The prognosis and management of primary thrombocytosis (PT) and secondary thrombocytosis (ST) are different. This study aims to evaluate the role of platelet function tests by light transmission platelet aggregometry (LTA), plasma von Willebrand factor antigen (vWF:Ag), ristocetin cofactor activity (vWF:RCo) and inflammatory markers [erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)] for the differentiation between PT and ST. Methods: This prospective study was carried out in patients with platelet counts greater than 450 x 109/L. Primary outcomes were the sensitivity and specificity of platelet function tests by LTA for the differentiation of PT and ST. Secondary outcomes were sensitivity and specificity of ESR, CRP, vWF:Ag, and vWF:RCo for the differentiation of PT and ST. Results: Fifty-two patients were enrolled onto the study of which 26 (50%) had PT. The sensitivity and specificity of epinephrine, collagen, and arachidonic acid (AA) induced abnormal LTA for the differentiation of PT from ST were sensitivity of 50%, 38.5%, 26.9% and specificity of 88.5%, 100%, 100% respectively. The sensitivity and specificity of abnormal ESR, CRP, and either abnormal ESR or CRP in the differentiation of ST from PT were sensitivity of 88.5%, 80.8%, 100% and specificity of 65.4%, 61.5%, 46.2% respectively. The sensitivity and specificity of low vWF:Ag and vWF:RCo in the differentiation of PT from ST were sensitivity of 7.69%, 42.3% and specificity of 100%, 88.5% respectively. Conclusions: Abnormal platelet function determined by LTA with collagen, AA, epinephrine had high specificity ratings enabling the differentiation between PT and ST. vWF:RCo, ESR and CRP levels could be helpful in differentiating between PT and ST.
The aim of this study was to elucidate the role of a non-canonical JAK2 mutation JAK2-T875N, which was identified by exome sequencing in a patient with essential thrombocytosis (ET) who had a family history of suspecting ET. Whole exome sequencing was performed on peripheral blood mononuclear cells and buccal swab-derived genomic DNA. Sanger sequencing was performed to confirm the variant. We evaluated the function of the mutation on JAK2 activity and downstream signaling (Erk, STATs) using JAK2-T875N-transfected or transduced cell lines. 293T cells transfected with JAK2 cDNA carrying V617F or T875N mutations showed increased levels of phosphorylated JAK2 and Erk. Enhanced STAT3 and STAT5 activity was confirmed by promoter assay. JAK2-T875N-transduced Ba/F3 cells showed increased cellular growth without IL-3 stimulation. To our knowledge, this is the first case of ET caused by JAK2-T875N mutation with a family history of thrombocytosis and cerebral infarction.
Essential thrombocytosis (ET) is a chronic myeloproliferative disorder with an unregulated surplus of platelets. Complications of ET include stroke, heart attack, and formation of blood clots. Although platelet-enhancing mutations have been identified in ET cohorts, genetic networks causally implicated in thrombotic risk remain unestablished. In this study, we aim to identify novel ET-related miRNA-mRNA regulatory networks through comparisons of transcriptomes between healthy controls and ET patients. Four network discovery algorithms have been employed, including (a) Pearson correlation network, (b) sparse supervised canonical correlation analysis (sSCCA), (c) sparse partial correlation network analysis (SPACE), and, (d) (sparse) Bayesian network analysis-all through a combined data-driven and knowledge-based analysis. The result predicts a close relationship between an 8-miRNA set (miR-9, miR-490-5p, miR-490-3p, miR-182, miR-34a, miR-196b, miR-34b*, miR-181a-2*) and a 9-mRNA set (CAV2, LAPTM4B, TIMP1, PKIG, WASF1, MMP1, ERVH-4, NME4, HSD17B12). The majority of the identified variables have been linked to hematologic functions by a number of studies. Furthermore, it is observed that the selected mRNAs are highly relevant to ET disease, and provide an initial framework for dissecting both platelet-enhancing and functional consequences of dysregulated platelet production.
Thrombocytosis has been associated with COPD prevalence and increased all-cause mortality in patients with acute exacerbation of COPD (AECOPD); but whether it is associated with morbidity in stable COPD is unknown. This study aims to determine the association of thrombocytosis with COPD morbidity including reported AECOPD, respiratory symptoms and exercise capacity.
Iron deficiency (ID) is globally prevalent, and apart from anemia is associated with thrombocytosis. While considered benign, studies linking thrombotic events with prior ID anemia suggest otherwise. Herein we used animal models to assess the influence of ID on thrombotic tendency. Sprague-Dawley rats were fed control or iron deficient diets and ferric carboxymaltose was used to reverse ID. Thrombosis was induced via stenosis of the inferior vena cava or damage to the right carotid artery using ferric chloride. Thrombi were evaluated histologically and via high frequency ultrasound in the venous model. ID consistently induced thrombocytosis alongside anemia. Venous thrombus growth and final dimensions in both arterial and venous thrombi were largest in ID. In both models, platelet numbers correlated with the final thrombus size, with ID thrombi having the largest platelet areas. Platelet function was also evaluated in surgically naive rats. Coagulability on thromboelastography and hemostasis on tail transection were augmented in ID. Platelet and plasma P-selectin expression were both higher in ID. Platelet adhesion and aggregation in ID was impaired under shear flow but was intact on static assays. Iron replacement therapy reversed all ID-related changes in hematological parameters, thrombus dimensions, and platelet assays. In summary, ID alone increases thrombotic tendency. Iron replacement therapy reverses these changes, making it a viable strategy for prevention of ID-related thrombotic disease. This may be of importance in patients with chronic illnesses which may already be at increased risk for thrombosis such as inflammatory bowel disease, chronic kidney disease, or cancer.
CALR mutations are identified in about 30% of JAK2/MPL-unmutated myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET) and primary myelofibrosis. Although the molecular pathogenesis of CALR mutations leading to MPNs has been studied using in vitro cell lines models, how mutant CALR may affect developmental hematopoiesis remains unknown. Here we took advantage of the zebrafish model to examine the effects of mutant CALR on early hematopoiesis and model human CALR-mutated MPNs. We identified three zebrafish genes orthologous to human CALR, referred to as calr, calr3a and calr3b. The expression of CALR-del52 and CALR-ins5 mutants caused an increase in the hematopoietic stem/progenitor cells followed by thrombocytosis without affecting normal angiogenesis. The expression of CALR mutants also perturbed early developmental hematopoiesis in zebrafish. Importantly, morpholino knockdown of mpl but not epor or csf3r could significantly attenuate the effects of mutant CALR. Furthermore, the expression of mutant CALR caused jak-stat signaling activation in zebrafish that could be blocked by JAK inhibitors (ruxolitinib and fedratinib). These findings showed that mutant CALR activates jak-stat signaling through an mpl-dependent mechanism to mediate pathogenic thrombopoiesis in zebrafish, and illustrated that the signaling machinery related to mutant CALR tumorigenesis are conserved between human and zebrafish.
Platelets have a key role in atherogenesis and its complications. Both hypercholesterolemia and increased platelet production promote atherothrombosis; however, a potential link between altered cholesterol homeostasis and platelet production has not been explored. Here we show that transplantation of bone marrow deficient in ABCG4, a transporter of unknown function, into Ldlr(-/-) mice resulted in thrombocytosis, accelerated thrombosis and atherosclerosis. Although not detected in atherosclerotic lesions, Abcg4 was highly expressed in bone marrow megakaryocyte progenitors (MkPs). Abcg4(-/-) MkPs had defective cholesterol efflux to high-density lipoprotein (HDL), increased cell surface expression of the thrombopoietin (TPO) receptor (c-MPL) and enhanced proliferation. These consequences of ABCG4 deficiency seemed to reflect disruption of negative feedback regulation of c-MPL signaling by the E3 ligase c-CBL and the cholesterol-sensing LYN kinase. HDL infusion reduced platelet counts in Ldlr(-/-) mice and in a mouse model of myeloproliferative neoplasm in an ABCG4-dependent fashion. HDL infusions may offer a new approach to reducing atherothrombotic events associated with increased platelet production.
Thrombocytosis (platelets ≥ 400K) is a common hematologic finding in gynecologic malignancies and associated with worse outcomes. Limited data exist on the prognostic capability of thrombocytosis in women with high-grade endometrial cancer (EC). Our objective was to describe the associations between elevated platelets at diagnosis, clinicopathologic features, and survival outcomes among women with high-grade, non-endometrioid EC. A review of the institutional cancer registry was performed to identify these women treated between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were performed using chi-square tests, Cox proportional hazards models, and the Kaplan-Meier method. A total of 271 women were included in the analysis. A total of 19.3% of women had thrombocytosis at diagnosis. Thrombocytosis was associated with reduced median overall survival (OS) compared with those not displaying thrombocytosis (29.4 months vs. 60 months, p < 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p < 0.01). While non-White women had shorter median OS for the whole cohort in the setting of thrombocytosis (29.4 months vs. 39.6 months, p < 0.01), among those with uterine serous carcinoma (USC), this finding was reversed, with decreased median OS in White women (22.1 vs. 16.4 months, p = 0.01). Thrombocytosis is concluded to have negative associations with OS and patient race.
Thrombus within the carotid artery usually occurs in vessels with severe atherosclerotic disease and may embolize to cause transient ischemic attacks and cerebral infarctions. The risk factors for carotid artery thrombus formation in the absence of atherosclerosis are not well characterized. A case series is presented that suggests an association of carotid artery thrombus with severe iron-deficiency anemia and thrombocytosis.
Carcinoma-associated thrombocytosis involves tumor production of mediators such as interleukin-6 (IL-6) and thrombopoietin (TPO) that increase thrombopoiesis and may play a role in tumor evasion and metastasis. Carcinoma-associated thrombocytosis is described in people, but has not been described in dogs.
The aim of the present meta-analysis study was to determine the association between pre-treatment thrombocytosis and prognosis of patients with endometrial cancer. Articles published prior to December 2018 containing information on platelet count and endometrial cancer were searched in the PubMed, Embase and the Cochrane Library databases. A platelet count of ≥350 or >400×109/l was considered to indicate thrombocytosis. Hazard ratios (HRs) with 95% CI were calculated using a random- or fixed-effects model to assess the strength of the associations. A Funnel plot and Egger's test were used to evaluate the publication bias and sensitivity analyses were performed to estimate the robustness of the present results by using Stata 13.0 software. A pooled analysis of 11 studies that met the inclusion criteria was performed, involving a total of 2,590 patients with endometrial cancer. The overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) time of patients with endometrial cancer who exhibited pre-treatment thrombocytosis were shorter than those in patients without pre-treatment thrombocytosis (OS, HR=2.25, 95% CI=1.26-4.00; PFS, HR=2.60, 95% CI=1.23-5.50; DFS, HR=2.23, 95% CI=1.45-3.42). However, pre-treatment thrombocytosis was not associated with disease-specific survival time in patients with endometrial cancer (HR=2.17, 95% CI=0.51-9.27; P=0.296). Subgroup analysis indicated that pre-treatment thrombocytosis was not associated with OS time in patients of Asian and European ethnicity. Furthermore, pre-treatment thrombocytosis (platelet count >400×109/l) was an independent predictor of OS, PFS and DFS regardless of the clinical stage.
Calreticulin (CALR) exon 9 frameshift mutations, commonly detected in essential thrombocythemia (ET) and primary myelofibrosis patients, activate signal transducer and activator of transcription (STAT) proteins in the presence of Myeloproliferative Leukemia Virus (MPL) and induce ET in vivo. Loss of the KDEL motif, an endoplasmic reticulum retention signal, and generation of many positively charged amino acids (AAs) in the mutated C-terminus are thought to be important for disease induction. To test this hypothesis, we generated mice harboring a Calr frameshift mutation using the CRISPR/Cas9 system. Deletion of 19-base pairs in exon 9 (c.1099-1117del), designated the del19 mutation, induced loss of the KDEL motif and generated many positively charged AAs, similar to human mutants. Calr del19 mice exhibited mild thrombocytosis, slightly increased megakaryocytes, and mild splenomegaly. In vitro experiments revealed that the murine CALR del19 mutant had a weaker ability to combine with murine MPL than the human CALR del52 mutant. Consequently, STAT5 activation was also very weak downstream of the murine mutant and murine MPL, and may be the reason for the mild disease severity. In summary, loss of the KDEL motif and positively charged AAs in the C-terminus of CALR is insufficient for MPL binding and ET development.
Mutations in calreticulin (CALR) have been reported to be key markers in the molecular diagnosis of myeloid proliferative neoplasms. In most previous reports, CALR mutations were analyzed by using Sanger sequencing. Here, we report a new, rapid, and convenient system for screening CALR mutations without sequencing.
There is an increasing number of studies showing that thrombocytosis-accompanying a variety of solid tumors including colorectal cancer (CRC)-is associated with shorter survival and earlier development of metastases. The mechanisms of cancer-associated thrombocytosis are not completely understood yet. The aim of our study was to evaluate the role of IL-6 in tumor development and thrombocytosis in mice with inflammation-induced CRC, using a CRISPR/cas9 IL-6 knockout (KO) strain. Adult male FB/Ant mice (n = 39) were divided into four groups: (1) IL-6 KO controls (n = 5); (2) IL-6 KO CRC model group (n = 18); (3) Wild-type (WT) controls (n = 6); and (4) WT CRC model group (n = 10). CRC model animals in (2) and (4) received azoxymethane (AOM)/dextran sodium sulfate (DSS) treatment to induce inflammation-related CRC. Plasma and liver tissues were obtained to determine platelet counts, IL-6 and thrombopoietin-1 (TPO) levels. In 1 WT and 2 IL-6 KO mice in vivo confocal endomicroscopy and 18F-fluorodeoxyglucose (FDG) PET/MRI examinations were performed to evaluate the inflammatory burden and neoplastic transformation. At the end of the study, tumorous foci could be observed macroscopically in both CRC model groups. Platelet counts were significantly elevated in the WT CRC group compared to the IL-6 KO CRC group. TPO levels moved parallelly with platelet counts. In vivo fluorescent microscopy showed signs of disordered and multi-nuclear crypt morphology with increased mucus production in a WT animal, while regular mucosal structure was prominent in the IL-6 KO animals. The WT animal presented more intense and larger colonic FDG uptake than IL-6 KO animals. Our study confirmed thrombocytosis accompanying inflammation-related CRC and the crucial role of IL-6 in this process. Significantly higher platelet counts were found in the WT CRC group compared to both the control group and the IL-6 KO group. Concomitantly, the tumor burden of WT mice was also greater than that of IL-6 KO mice. Our findings are in line with earlier paraneoplastic IL-6 effect suggestions.
Inflammatory stimuli have divergent effects on peripheral platelet counts, although the mechanisms of thrombocytopenic and thrombocytotic responses remain poorly understood. A candidate gene approach targeting 326 polymorphic genes enriched in thrombopoietic and cytokine signaling pathways was applied to identify single nucleotide variants (SNVs) implicated in enhanced platelet responses in cohorts with reactive thrombocytosis (RT) or essential (myeloproliferative neoplasm [MPN]) thrombocytosis (ET). Cytokine profiles incorporating a 15-member subset, pathway topology, and functional interactive networks were distinct between ET and RT, consistent with distinct regulatory pathways of exaggerated thrombopoiesis. Genetic studies using aggregate (ET + RT) or ET-restricted cohorts identified associations with 2 IFNA16 (interferon-α16) SNVs, and the ET associations were validated in a second independent cohort (P = .0002). Odds ratio of the combined ET cohort (n = 105) was 4.92, restricted to the JAK2V617F-negative subset (odds ratio, 5.01). ET substratification analysis by variant IFNA16 exhibited a statistically significant increase in IFN-α16 levels (P = .002) among 16 quantifiable cytokines. Recombinantly expressed variant IFN-α16 encompassing 3 linked non-synonymous SNVs (E65H95P133) retained comparable antiviral and pSTAT signaling profiles as native IFN-α16 (V65D95A133) or IFN-α2, although both native and variant IFN-α16 showed stage-restricted differences (compared with IFN-α2) of IFN-regulated genes in CD34+-stimulated megakaryocytes. These data implicate IFNA16 (IFN-α16 gene product) as a putative susceptibility locus (driver) within the broader disrupted cytokine network evident in MPNs, and they provide a framework for dissecting functional interactive networks regulating stress or MPN thrombopoiesis.
Background: The prognostic and clinicopathological role of pretreatment thrombocytosis in cancer has been widely studied, but conclusions in endometrial cancer (EnCa) remain controversial. Therefore, we conducted a meta-analysis to assess the pathologic and prognostic impacts of pretreatment thrombocytosis in patients with EnCa. Methods: We searched PubMed, Embase, SpringerLink, ScienceDirect and China National Knowledge Infrastructure databases. Pooled HR or OR with their 95% CIs were applied to assess the association of pretreatment thrombocytosis with survival outcomes and clinical parameters of EnCa patients. Results: In total, 10 studies containing 2,995 cases of EnCa met the criteria. The results suggested that pretreatment thrombocytosis was significantly associated with high International Federation of Gynecology and Obstetrics (FIGO) stage (pooled OR 3.45, 95% CI 1.68-7.08, P=0.001), poor tumor differentiation (pooled OR 2.00, 95% CI 1.22-3.29, P=0.006), lymph-vascular space invasion (pooled OR 2.04, 95% CI 1.35-3.07, P=0.001); myometrial invasion (pooled OR 2.14, 95% CI 1.39-3.32, P=0.001); cervical involvement (pooled OR 2.54, 95% CI 1.56-4.15, P=0.000) and lymph node metastasis (OR 3.15, 95% CI 1.71-5.80, P=0.001). No significant difference existed between pretreatment thrombocytosis and overall survival (P=0.012), cancer/disease-specific survival (P=0.07) or disease-free survival (P=0.25). Conclusion: pretreatment thrombocytosis was associated with advanced clinicopathological features in patients with EnCa, which may serve as a potential therapeutic target for EnCa.
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